Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53

The cellular function of p53 is complex, It is well known that p53 plays a key role in cellular response to DNA damage. Moreover, p53 was implicated i n cellular senescence, and it was demonstrated that p53 undergoes modificat ion in senescent cells, However, it is not known how these modifications af fect the ability of senescent cells to respond to DNA damage. To address th is question, we studied the responses of cultured young and old normal dipl oid human fibroblasts to a variety of genotoxic stresses. Young fibroblasts were able to undergo p53-dependent and p53-independent apoptosis. In contr ast, senescent fibroblasts were unable to undergo p53-dependent apoptosis, whereas p53-independent apoptosis ass only slightly reduced. Interestingly, instead of undergoing p53-dependent apoptosis, senescent fibroblasts under went necrosis, Furthermore, we found that old cells were unable to stabiliz e p53 in response to DNA damage. Exogenous expression or stabilization of p 53 with proteasome inhibitors in old fibroblasts restored their ability to undergo apoptosis. Our results suggest that stabilization of p53 in respons e to DNA damage is impaired in old fibroblasts, resulting in induction of n ecrosis. The role of this phenomenon in normal aging and anticancer therapy is discussed.